This invention relates to a method and kit for regulating menses and/or reducing the side effects, such as unscheduled bleeding, in pre-, para- and post-menopausal females on low dosage estrogen and/or with estrogen-progestin therapy and for achieving oral contraception in gonadal female mammals.
Although inhibition of ovulation in the form of estrogen/progestin combination oral contraceptives has been the most effective strategy for achieving reversible pharmacological fertility control in women, because of the known adverse side-effects associated with long term contraception by this method, especially in women who smoke in the 40-44 age group, over the years interest in achieving contraception at lower estrogen doses has developed.
Thus, during the over 30 year history of combined estrogen/progestin oral contraception, there has been a steady downward adjustment of the daily estrogen dosage, both for oral contraceptive purposes in premenopausal female and for estrogen replacement therapy in post-menopausal females. See, e.g., EP-A-0 253,607, which discloses, as a preferred embodiment, administering to pre-menopausal females daily a tablet containing 1 mg of 17β-estradiol and 0.075 ml of levonorgestrel for 23 or 24 (23-26) days followed by 5 or 4 (2-5) “pill free” or blank-pill days, for a total of 28 days per cycle, and the references cited therein, the disclosures of all of which are incorporated herein by reference.
Concurrently, although the progestin component has been lowered somewhat also, reduced androgenicity has remained an ongoing priority. Together, these adaptations of formulation have been presented in a variety of regimens, both monophasic and multiphasic. As a result, today's oral contraceptives are much safer with regard to the incidence and severity of estrogen-linked clotting disorders, as well as the cumulative impact of more “lipid friendly” progestins that maintain high density lipoprotein cholesterol levels in circulation. See, Spellacy, W N et al.,; “Am J Obstet Gynecol” 1980; 137; 109; Scott, J Z et al., “Fertil Steril” 1978; 30:141; Mishell, DR Jr. et al., “J Reprod Med.” 1990; 35 (Suppl. 4): 447-481; Speroff L., “Contemp Obstet Gynecol” 1991; 36:65; Meilis G B et al., “Contraception” 1991; 43; 23; and Stamplfer M J, Willett W C et al., “Am J. Obstet Gynecol” 1990; 163: 285.
This evolution of oral contraceptive formulations advanced most rapidly in Europe and has been steadily emerging in America as well. Indeed, the accumulating data based on oral contraceptive pills containing only 20 to 35 μg of estrogen per day spurred the Food and Drug Administration's Fertility and Maternal Health Drugs Advisory Committee to indicate low dose oral contraceptives for healthy, non-smoking women during the perimenopausal years (such as ages 35 to 50) [See Mishell (1990) and Speroff (1991)], supra; U.S. Food and Drug Administration, Advisory Committee on Maternal and Reproductive Health, 1989, Rockville, Md.; and Rosenberg, L. et al. JAMA 1985; 253:2965. In Japan, oral contraceptives are now being evaluated for safety and efficacy criteria for the first time, with anticipation of general availability to physicians and patients within about one year.
In addition to maintenance of contraception efficacy when the female is gonadal a principal issue involved when considering lowering the daily dose of estrogen-progestin medications in oral contraceptives even lower, is avoidance of further erosion in the control of endometrial bleeding. Whereas even the lowest dose oral contraceptive products available now have demonstrated sustained contraception efficacy, overall the incidence of bleeding control problems, which manifest themselves both in breakthrough bleeding (untimely flow or spotting) or withdrawal amenorrhea during the “pill free” week (expected menses), has increased as estrogen/progestin doses are reduced. See Gray, R H. in “Endometrial Bleeding and Steroidal Contraception”; Diczfalusy E, Fraser R S, Webb F T E (Eds). Bathe, England: Pittman Press; 1990: 14-19, and Cullbey G. et al., “Contraception” 1982; 26:229. The same problem is associated with low dosage hormonal replacement therapy (HRT).